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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Yu-Wen Zhang, M.D., Ph.D. Signal Transduction and Molecular Medicine Dr. Zhang received his M.D. degree from Fudan University Shanghai Medical College, China, in 1989 and his Ph.D. degree in medical science from Kyoto University, Japan, in 1997. He served as a postdoctoral fellow in the laboratory of Yoshiaki Ito at the Institute for Virus Research of Kyoto University between 1997 and 1999, and then in the laboratory of George Vande Woude at VARI from 1999 to 2002. In 2002 he became a Research Scientist, and in 2010, a Senior Research Scientist at VARI. He was promoted to Research Assistant Professor in April 2013. From left: Zhang, Staal, Rietberg Staff Ben Staal, M.S. Student Skyler Rietberg 44

Zhang Research Interests Receptor tyrosine kinases (RTKs) are crucial for many developmental and physiological processes, and their inappropriate activation can lead to cancer and other diseases. The intensity and duration of an RTK signal determines how cells will respond and what the biological outcome will be. Under normal conditions, RTK signaling needs timely attenuation via mechanisms such as receptor turnover, phosphatase-mediated dephosphorylation, and negative feedback inhibition. We are interested in understanding how signaling driven by the RTKs, especially EGFR and MET, is regulated and why deregulation of such signaling affects disease development, progression, and therapy response. Both EGFR and MET are often aberrantly activated in human cancers. In non-small-cell lung cancer (NSCLC) cells, these two RTKs are often coexpressed and may cross-talk in driving tumorigenesis and metastasis. Using NSCLC xenograft models, we have found that combined inhibition of MET and EGFR results in a better therapeutic efficacy by enhancing antiproliferation, inducing apoptosis, or overcoming drug resistance in a cellular context–dependent manner. We will continue to study how receptor cross talk and tumor heterogeneity influence malignant processes and drug resistance. Mitogen-inducible gene-6 (Mig-6) inhibits the signaling driven by RTKs via a negative feedback loop: EGF induces Mig-6 expression through activation of the EGFR-RAS-MAPK signaling cascade, and Mig-6 attenuates the signaling by modulating the activity of EGFR and its downstream molecules. Mig-6 expression is altered in various human cancers, and we have identified Mig-6 mutations in several lung cancer samples (although this is rare). A tumor suppressor role for Mig-6 is also supported by the fact that its deletion in mice results in neoplasia in multiple organs/tissues. Mig-6 is essential for maintaining joint homeostasis, and mice with a Mig-6 deficiency develop degenerative joint disease in multiple synovial joints. We are investigating how Mig-6 exerts its tumor suppressor activity and why its loss in mice leads to joint degeneration. Recent Publications Pest, Michael A., Bailey A. Russell, Yu-Wen Zhang, Jae-Wook Jeong, and Frank Beier. In press. Loss of mitogen-inducible gene 6 results in disturbed cartilage and joint homeostatis. Arthritis and Rheumatology. Joiner, Danese M., Kennen D. Less, Emily M. Van Wieren, Yu-Wen Zhang, Daniel Hess, and Bart O. Williams. 2014. Accelerated and increased joint damage in young mice with global inactivation of mitogen-inducible gene 6 (Mig-6) after ligament and meniscus injury. Arthritis Research and Therapy 16(2): R81. Staal, Ben, Bart O. Williams, Frank Beier, George F. Vande Woude, and Yu-Wen Zhang. 2014. Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chrondrocyte proliferation. Proceedings of the National Academy of Sciences U.S.A. 111(7): 2590–2595. Merchant, Mark, Xiaolei Ma, Henry R. Maun, Zhong Zheng, Jing Peng, Mally Romero, Arthur Huang, Nai-ying Yang, Merry Nishimura, et al. 2013. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proceedings of the National Academy of Sciences U.S.A. 110(32): E2987–E2996. Zhang, Yu-Wen, Ben Staal, Curt Essenburg, Steven Lewis, Dafna Kaufman, and George F. Vande Woude. 2013. Strengthening context-dependent anticancer effects on non–small cell lung carcinoma by inhibition of both MET and EGFR. Molecular Cancer Therapeutics 12(8): 1429–1441. Zhang, Yu-Wen, and George F. Vande Woude. 2013. MIG-6 and SPRY2 in the regulation of receptor tyrosine kinase signaling: balancing act via negative feedback loops. In Future Aspects of Tumor Suppressor Genes, Yue Chang, ed. Rijeka, Croatia: InTech, pp. 199–221. 45

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